Journal of Pain and Symptom Management
Volume 19, Issue 6 , Pages 446-456, June 2000

High Level of Fatigue in Lymphoma Patients Treated With High Dose Therapy

  • Heidi Knobel, MD

      Affiliations

    • Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway
    • Corresponding Author InformationAddress reprint requests to: Heidi Knobel, MD, Unit for Applied Clinical Research, The Faculty of Medicine, Norwegian University of Science and Technology, Trondheim University Hospital, N-7006 Trondheim, Norway
    • ,
  • Jon Håvard Loge, MD

      Affiliations

    • Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway
    • Department of Behavioral Sciences in Medicine, University of Oslo, Oslo, Norway
    • ,
  • Tone Nordøy, MD

      Affiliations

    • Department of Oncology, Tromsø University Hospital, Tromsø, Norway
    • ,
  • Arne L. Kolstad, MD, PhD

      Affiliations

    • Department of Oncology, Tromsø University Hospital, Tromsø, Norway
    • ,
  • Terje Espevik, MD, PhD

      Affiliations

    • The Faculty of Medicine, and Institute of Cancer Research, Norwegian University of Science and Technology, Trondheim, Norway
    • ,
  • Stein Kvaløy, MD, PhD

      Affiliations

    • Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway
    • The Norwegian Radium Hospital, Oslo, Norway
    • Palliative Care Unit, Department of Oncology, Trondheim University Hospital, Trondheim, Norway
    • ,
  • Stein Kaasa, MD, PhD

      Affiliations

    • Unit for Applied Clinical Research, Norwegian University of Science and Technology, Trondheim, Norway
    • The Norwegian Radium Hospital, Oslo, Norway
    • Palliative Care Unit, Department of Oncology, Trondheim University Hospital, Trondheim, Norway

Accepted 14 July 1999.

Article Outline

Abstract 

With the success of high dose therapy supported by autologous bone marrow transplantation (ABMT) for malignant lymphomas, medical late-effects and secondary effects on subjective health, like fatigue, are of concern. Fatigue is poorly understood and correlates have been barely addressed. Health-related quality of life (HRQL), fatigue, and correlates to fatigue, including endocrinological status and serum levels of interleukin-6, tumor necrosis factor, and soluble tumor necrosis factor receptors, were investigated in a cross-sectional study of 33 lymphoma patients (median age 39 years) 4–10 years after ABMT. The survivors were compared to general population norms. Fatigue was highly prevalent, and females reported significantly more fatigue and impaired HRQL compared to males and the normal population. Gonadal dysfunction was found in the majority of the patients, but no statistically significant endocrinological or immunological associations with fatigue could be demonstrated. The high level of fatigue among female long-term survivors after ABMT may be related to the gonadal dysfunction, but further studies of possible mechanisms behind fatigue are necessary.

Keywords:  Fatigue, cancer, quality of life, high dose therapy, autologous bone marrow transplantation, cytokines, sex hormones

 

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Introduction 

High-dose therapy supported by allogenic or autologous bone marrow transplantation (ABMT) or peripheral progenitor cells support has rapidly gained acceptance as a curative treatment option for a number of cancers like leukemia and lymphoma. From being a highly experimental procedure, only given in advanced stages of malignant diseases, the utility of high dose therapy with allogenic and autologous stem cell support has expanded during the last several years,1, 2, 3 leading to an increasing number of long-term survivors. These therapies are generally performed in young patients with long life expectancy. Despite the clinical success achieved with this treatment, the long-term toxic effects are of concern .1, 2, 3, 4, 5, 6, 7, 8

Mortality and somatic-related morbidity have been the main outcomes in the clinical investigations after high dose therapy with stem cell support. During recent years, however, attention has been directed towards health-related quality of life (HRQL) as an endpoint after such treatment.5, 6, 7, 8

HRQL is defined as a multidimensional concept consisting of physical, psychological and social dimensions.9 Fatigue or vitality is a subdomain of HRQL, and is included in most HRQL-instruments. Fatigue is usually defined as a subjective phenomenon, and in the absence of objective measures, measurements of fatigue rely on subjective reports from patients themselves.10 Patients in several follow-up studies after BMT report their HRQL as rather good.8 However, deficits in specific domains in HRQL are frequently reported.8, 11 Fatigue was one of the three most frequently reported current problems in a study of 125 adult long-term survivors (6–18 years) of BMT/ABMT.12 In a study of 29 adults 1–8 years after BMT, 76% reported “feeling tired”.13 Further, 50% reported fatigue and reduced energy level in a study of 24 adults 12–38 months post-BMT.14 The majority of these studies may be regarded as inconclusive with regard to fatigue because specifically designed instruments assessing fatigue were not employed. Measuring fatigue by single items generally have poor reliability, and a large number of patients are required in order to detect quite modest changes of fatigue level. During recent years, specific fatigue instruments have been developed, and these instruments are preferred in clinical research.15

Fatigue is also a prevalent symptom in the general population; prevalence rates between 11% to 45% have been reported. In a randomized survey in the Norwegian population, 11% were classified as fatigue cases using the Fatigue Questionnaire (FQ).16 Interpretation of fatigue data among cancer survivors without accounting for the high prevalence in the normal population might invalidate the conclusions. In a recent study of 459 Hodgkin's disease survivors (HDS) 12 years post treatment, the FQ was used. In this cohort, more than twice as many HDS (26%) were fatigued as compared to the normal population (11%).17

The pathogeneses of fatigue remain uncertain. Several somatic conditions, such as permanent changes in the endocrine or immune systems, hematological changes, neurologic impairments, or reduced heart and/or lung function, may cause fatigue.18 To our knowledge, no one has investigated biological correlates of persisting fatigue among long-term cancer survivors.19 The possible biological changes may either be related to the malignant disease itself or to the side effects from the treatment. In some studies, fatigue has been found to be associated with increased levels of the cytokines interleukin-1 (IL-1) and tumor necrosis factor (TNF).20, 21, 22 Due to the presence of cytokines in the brain, it has been postulated that they might modulate neural function, as they are modulators of the immune system.23 Endocrine causes of cancer-related fatigue also have not been properly investigated. Although gonadal dysfunction is a well-known medical complication of ABMT,24 it has never been correlated with fatigue. Low testosterone levels in patients with advanced cancer are found to be common,25, 26 but an association with fatigue has never been investigated.

The primary aim of this study was to assess the prevalence of fatigue and HRQL in patients treated with high dose therapy and ABMT, and to compare these patients with norms from the general population. Furthermore, we wanted to explore the relationship between fatigue and disease and treatment variables, levels of cytokines, and endocrine abnormalities.

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Methods 

Patients 

From 1987 until 1993, all 85 cases of malignant lymphomas requiring ABMT in Norway were treated at the Norwegian Radium Hospital. In January 1997, 46 patients were alive, in complete remission (CR), and invited by mail to participate in this study. Few studies on late side effects more than 3 years after ABMT exist5 and we decided that a follow-up period of 3 years or more was appropriate to assess late side effects. One patient refused to see a new doctor, another answered too late for inclusion, and one had moved abroad. Four patients did not answer. Thirty-eight of the remaining 39 patients completed the mailed questionnaires. Before the clinical work-up, three patients declined to participate due to hospitalization (because of cerebral insult, myelodysplastic syndrome, and major psychiatric problems, respectively). Two of the blood samples were damaged during transportation. Thirty-three serum samples were valid for use. Of 38 patients who returned the questionnaires, the questionnaires from those 33 patients with valid serum tests were chosen. Of those 33 patients, 32 completed the entire quality of life questionnaire and all 33 completed the entire Fatigue Questionnaire.

Median age at study was 39 years, with a median observation time since diagnosis of 8 years. Median time since ABMT was 6 years (Table 1). The majority of the patients were in stage IVA. Sixteen patients with Burkitts lymphoma or lymphoblastic lymphoma received ABMT as a part of the primary treatment after a first remission. The remaining 17 patients with intermediate grade NHL, low grade NHL, or Hodgkin's disease received high dose therapy after a second or later remission. It was decided to divide the patients into two groups according to these criteria when assessing the relationship between diagnosis and treatment to fatigue. All patients received combination chemotherapy according to standard treatment protocols as part of the induction procedure before the high dose regimen, or as primary treatment alone. Cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) was the most frequently used chemotherapy regimen, as primary treatment alone, or in combination with high dose methotrexate as part of the preparation procedure. Fourteen of those 16 patients who were treated with high dose chemotherapy in first remission received high dose methotrexate as part of the induction therapy, and eight of them also received methotrexate intrathecally. Cyclophosphamide and total body irradiation (TBI) was applied as high dose therapy in 29 patients, and vepecid, cyclophosphamide, cytosar, BCNU (BEAC) in 4 patients.

Table 1. Patient Characteristics (n = 33)
n (%)
Age at time of study (yrs)39 (18-59)a
Age at time of ABMT (yrs)35 (15-55)a
Gender
Male18 (55)
Female15 (45)
Years after diagnosis
3–612 (36)
7–1020 (61)
15–201 (3)
Years after high dose chemotherapy
4–624 (73)
7–109 (27)
Diagnosis
NHL, high grade, 1. remission (Burkitts lymphoma/Lymphoblastic lymphoma)16 (49)
NHL, intermediate/low grade /HD 2. or later remission17 (51)
Clinical stageb (n = 30)
I6 (20)
II3 (10)
III7 (23)
IV14 (47)
Substage (n = 29)
A17 (52)
B12 (36)
High dose regimen
Cyclophosphamide and TBI29 (88)
BEAC4 (12)
HD Hodgkins disease NHL Non Hodgkins Lymphoma.

a Median (range)

b At time of diagnosis according to Ann Arbor classification.

Measures 

A questionnaire was mailed to the patients. Non-responders were reminded once through a telephone call after one week. The questionnaire contained the following measures:

Fatigue Questionnaire (FQ) 

The Fatigue Questionnaire is an instrument specifically designed for assessing fatigue. It was developed for a hospital study of Chronic Fatigue Syndrome (CFS),27 and was later refined in a validation study in which all items specifically related to CFS were removed.15 Later, it was used in several epidemiological studies.16 FQ is a two-dimensional instrument, consisting of 11 items measuring physical and mental fatigue. Additionally, two items ask about the duration and extent of fatigue symptoms. Each item has four response categories, scored 0, 1, 2, 3. Total fatigue (TF, all items) (range 0–33), physical fatigue (PF, seven items) (range 0–21) and mental fatigue (MF, four items) (range 0–12) are the sums of the scores for the whole scale or the physical and mental subscale, respectively.

The reliability of FQ was assessed by estimates of internal consistencies of the questionnaire. Cronbach's alpha scores were 0.92 (PF), 0.84 (MF) and 0.89 (TF), confirming the findings of previous validation study.15

European Organization for Research and Therapy of Cancer (EORTC) QLQ-C30 

EORTC QLQ-C30 was used to measure HRQL.9 The instrument consists of six functional scales that measure physical, role, cognitive, social, and emotional function, as well as overall Quality of Life. Three symptom scales measure fatigue, pain, and emesis, and six single items measure appetite loss, sleep disturbance, dyspnea, diarrhea, constipation, and financial impact.

All the scales and item scores were linearly transformed to 0–100 point scales.28 For the functional scales and global health/Quality of Life scale, higher score represents better functioning and quality of life. Higher scores on the symptom scales correspond to more symptoms.

In two previous studies norms for the FQ and EORTC QLQ-C30 had been established from two random surveys of the Norwegian population.16, 29 Significant differences in the norms according to age and gender were found.16, 29 A decline in physical functioning and more symptoms were found with increased age.29 The prevalence and level of fatigue increased with increasing age,16 and women reported worse HRQL and more fatigue than men did. Due to the age and gender differences, an adjustment for these variables was performed. Responders in the older age groups, above 60 years, were deleted from the norms in order to match the ABMT sample, and a gender-specific stratified analysis was performed.

Sociodemographics, diagnosis, stage, histology, and treatment were based on the patients records and on the personal interview.

Blood Sampling Protocol 

Interleukin 6 (IL-6), TNF and soluble TNF-p55 and p75 receptor values were determined in serum samples from blood drawn into sterile vacuum tubes without additives. Tubes were immediately immersed in melting ice, and serum samples were stored at −70°C in multiple aliquots until analysis. Serum samples for cytokine analysis were frozen and thawed only once.

Measurement of IL-6 

IL-6 was determined by the IL-6 dependent mouse hybridoma cell line B13.29 clone B9.30 Serial dilutions of serum samples were incubated for 72 hours with IL-6 dependent cells. Viability was measured in a calorimetric assay with the MTT tetrazolium salt (Sigma Chemical Co, St. Louis, Missouri, USA).31 Recombinant IL-6 was included as a standard. We preferred the measurement of IL-6 instead of IL-1 since IL-6 is very stable, and like IL-1, reflects an immune activation.

Measurement of TNF 

TNF was determined by its cytotoxic effect on the fibrosarcoma cell line WEHI 164 clone.32 Recombinant TNF was included as a standard.

Immunoassays for detection of soluble TNF receptors (sTNFR) in serum 

The TNF receptors p55 and p75 were analyzed by immunoassay.33 Immunoplates were coated with the monoclonal antibodies IV4E and 3H5, recognizing non-TNF binding sites of p55 and p75 TNFR, respectively. Recombinant human p55 and p75 (provided by Dr. H. Loetscher, F.Hoffmann-La Roche, Basel, Switzerland) served as standard. Measurement of soluble TNR receptors bear some advantage compared to direct quantification of TNF. sTNR are very stable, can be determined in stored sera, and allow some insight into TNF biology. Both receptors sTNF p55 and p75, as well as TNF, are found to be elevated in cancer patients.37, 38

As reference group for IL-6 and sTNFR p55 and p75, serum samples from 10 healthy individuals were used. The reference population was selected in accordance to age and gender distribution in the patient sample.

Statistical Analysis 

Bivariate associations were studied by χ2 statistics (nominal categorical variables), two-tailed t-test (independent samples), or Pearsons correlation where appropriate. Differences in cytokines and cytokines receptor levels between groups were tested by non-parametric tests. Wilcoxon rank sum test (two-tailed) was used for comparison of the two groups; the Kruskal-Wallis test was used when > 2 groups were compared. The correlation coefficients (r) were calculated using Spearman's rank test. A p-value of 0.05 was chosen to indicate statistical significance. In the analyses of the EORTC QLQ-C30, a difference above 10 is considered clinically significant,29, 34 while 7–10 might be considered as questionably significant. In order to interpret differences in mean estimates of fatigue, a comparison with general population scores might be used. In a previous study, we have reported mean differences between subcohorts of the general population.16 By comparing the most healthy subcohort with those with poorest health, differences of 3.0, 2.6, and 0.4 were found for TF, PF, and MF, respectively.

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Results 

Fatigue 

Patients cured of malignant lymphoma were significantly more fatigued than the Norwegian reference population (Table 2). The difference was most prevalent for physical fatigue. The mean total fatigue score (TF) was 17.9 and 12.8 among the women and men, respectively (p = 0.02). A similar pattern was found for physical fatigue (p = 0.01), whereas small differences between the genders were found in mental fatigue. Women reported significantly more physical fatigue and total fatigue as compared to the reference population. For the male population, no differences were found between patients and reference population. Tumor stage or substage at time of diagnosis was not associated with fatigue, nor was observation time since treatment or the treatment burden. Patients treated with high dose chemotherapy during the second or later remission who were exposed to a considerable treatment burden did not report significantly more fatigue than patients treated during the first remission (PF 8.7 vs. 11.3; TF 13.4 vs. 16.9, p = 0.10). A trend was observed, however, among women. Those treated with high dose chemotherapy during the first remission reported more physical and total fatigue than those treated during later remissions (PF 14.1 vs. 9.7; TF 20.8 vs. 14.7; p = 0.05 and p = 0.07 respectively). The majority (14 of 16 patients) of these patients received high dose methotrexate, and eight of them also received methotrexate intrathecally as part of the preparative regimen.

Table 2. Fatigue in Patients and in Reference Population
FemalesMalesTotal
FatiguePatients Mean (95% CI)Reference Population Mean (95% CI)Patients Mean (95% CI)Reference Population Mean (95% CI)All patients Mean (95% CI)Reference Population Mean (95% CI)
Physical12.1a,b (9.6–14.5)8.0a (7.8–8.2)8.2b (6.3–10.0)7.4 (7.2–7.6)9.9c (8.4–11.5)7.7c (7.6–7.8)
Mental5.9 a(4.6–7.2)4.3a (4.2–4.4)4.6 (3.5–5.7)4.3 (4.2–4.3)5.2c (4.4–6.0)4.3c (4.2–4.4)
Total17.9a,c (14.4–21.5)12.3a (12.1–12.6)12.8c (10.0–15.5)11.6 (11.3–11.9)15.1a (12.9–17.4)12.0a (11.8–12.2)
n1592118874331786

a p < 0.001 for differences in mean scores between patients and reference population.

b p < 0.01 for differences in mean scores between gender.

c p < 0.05 for differences in mean scores between gender, and between patients and reference population.

Health-Related Quality of Life 

Patients reported reduced role function, cognitive function, social function and financial difficulties compared to the general population (Table 3). A questionable reduced global quality of life, emotional function and more dyspnea also were found. Diarrhea was the only symptom reported more frequently by the patients. Women reported poorer HRQL than men when compared to gender-specific references. The differences between patients and norms were ten or more in seven scales and items: global quality of life (women only), cognitive function (women), emotional function (women), role and social function (both genders), diarrhea (women), and financial impact (both genders). Fatigue was equally reported by both genders, and did not differ significantly compared with the normal population.

Table 3. EORTC QLQ-C30 Mean Scores by Gender and Age
ABMT (n = 32)Reference Population (n = 1404)ABMT Female (n = 15)Female Reference Population (n = 636)ABMT Male (n = 17)Male Reference Population (n = 768)
Global QOL (QOL2)69a77a63757479
Functioning scaled
Physical (PF)929588939596
Role (RF)76b87b74857689
Emotional (EF)75a82a66798385
Cognitive (CF)75c89c69888089
Social (SF)68c87c64857190
Symptom scalee
Fatigue (FA)342835323325
Nausea/vomiting (NV)447523
Pain (PA)201822221915
Dyspnea (DY)19a11a18152013
Insomnia (SL)201824211615
Appetite loss (AP)147169126
Constipation (CO)108912125
Diarrhea (DI)21b9b299149
Financial difficulties (FI)22c9c2711187

a p < 0.05 for differences in mean scores, patients and reference group.

b p < 0.01 for differences in mean scores, patients and reference group.

c p < 0.001 for differences in mean scores, patients and reference group.

d Higher scores indicates better functioning.

e Higher scores indicates more symptoms.

Fatigue and Employment Status 

Eighteen patients were employed full-time, whereas 6 and 8 patients, respectively, were part-time employed or not employed at all (employment information missing in 3 patients). Eight of those patients who were partly or not employed were disabled after the disease, and 3 patients were getting through their education. There were clinically and statistically significant differences in fatigue levels between those who were employed full-time (PF 8.3, MF 4.7, TF 12.9), employed part-time (PF 10.7, MF 5.3, TF 16.0), and not employed at all (PF 14.4, MF 6.9 TF 21.3) (p = 0.01; 0.05, and 0.02 PF, MF, and TF, respectively). Patients who were disabled reported more fatigue than those who were full- or part-time employed (PF 14.4, MF 7.1, TF 21.5).

Endocrine Status 

More than half the women had elevated serum levels of follicle-stimulating hormone (FSH) and leutenizing hormone (LH), while serum levels of estradiol were decreased in 13 of the females (Table 4). Two women were postmenopausal, but were not substituted. Among the men, FSH and LH were elevated in 13 and 6 patients respectively, and low levels of testosterone were found in 6 patients.

Table 4. Endocrine Status (Serum Levels) after ABMT
Females (n = 15)Males (n = 17)
Hb
< 11.5 g/dl females1/15
< 13 g/dl male 5/17
TSH > 4.0 mIE/l)1/15
FT4 < 9 pmol/L)1/15
FSH
> 20 IU/L females9/15
> 12 IU/L males 13/17
LH
> 15IU/L females8/15
> 12 IU/l male 6/17
Estradiol < 0.33nmol/L13/15
Testosterone < 12 nmol/l 6/17

Gonadal dysfunction expressed by high levels of FSH (>20 IU/L for women, > 12 IU/L for men) and low levels of estradiol (<0.33 nmol/l; women) and testosterone (<12 nmol/l; men) were compared to levels of fatigue to test whether gonadal dysfunction was related to fatigue among ABMT patients. Nine patients had reduced ovarian functioning, and the levels of fatigue did not differ from those with normal hormone levels (5 patients) (PF 12.6, MF 6.6, TF 19.1 vs. PF 11.3, MF 4.8, TF 16.2; n.s.). A similar finding occurred in men with no differences in fatigue levels between patients with impaired (n = 4) versus males with normal gonadal function (n = 14) (PF 8.8, MF 4.8, TF 13.5 vs. PF 8.0, MF 4.6, TF 12.6; n.s.)

Thyroid function was not impaired, and only 1 woman and 5 men had a slightly reduced hemoglobin level. No association between hemoglobin level and fatigue was found.

Serum Levels of IL-6, TNF, and sTNFR 

The serum levels of TNF were below 600 pg/ml in 31 of 33 patients. Only two male patients had detectable biological activity of TNF, with serum levels of 870 pg/ml and 963 pg/ml. The clinical status and fatigue levels of those patients did not differ from the rest of the study population. Serum levels of IL-6, sTNFR-p55, and sTNFR-p75 were slightly elevated in all clinical groups of lymphoma patients compared to normal controls (Table 5). A trend was found in the difference of p75 receptors with advanced stage (p = 0.07). Treatment burden or time since treatment did not seem to have any influence on levels of the measures.

Table 5. Serum Levels of sTNFRs and IL-6 in Patients Cured of Malignant Lymphoma and Control Groups (Normal Population)
sTNFRIL–6
p55 median (range)p75 median (range)median (range)
Controls (n = 10)1.05 (0.70–1.50)1.50 (0.90–2.30)4.80 (3.20–11.0)
Patients (n = 33)1.39 (0.60–2.20)1.60 (0.70–2.90)4.90 (2.70–11.0)
Fatigue levela
high (n = 17)1.30 (0.60–2.20)1.60 (0.70–2.90)4.90 (2.70–10.80)
low (n = 16)1.30 (0.60–1.90)1.60 (0.90–2.40)5.05 (2.90–11.00)
Burkitts lymphoma/lymphoblastic lymphoma1.15 (0.30–1.90)1.45 (0.20–2.40)5.70 (2.70–11.00)
Intermediate grade/Low grade Lymphoma /HD Stage1.30 (1.10–2.20)1.70 (1.30–2.90)4.90 (2.70–10.80)
I (n = 6)0.95 (0.80–1.40)1.25 (0.90–2.00))4.50 (3.60–8.30)
II (n = 3)1.30 (0.70–0.60)1.60 (0.70–1.90)5.80 (2.70–6.80)
III (n = 7)1.30 (1.10–1.80)1.80 (1.60–2.30)4.60 (3.20–10.80)
IV (n = 14)1.25 (0.60–1.90)1.60 (0.70–2.40)5.05 (2.70–11.0)
Substage
A (n = 17)1.20 (0.60–1.80)1.60 (0.70–2.30)5.40 (2.70–10.80)
B (n = 12)1.30 (0.60–1.90)1.60 (0.70–2.40)4.85 (2.70–11.0)

a Mean total fatigue score, high: TF 19.6; mean total fatigue score, low: TF 10.5.

There were no statistically significant correlation between fatigue (TF) and serum levels of IL-6, TNF, sTNFR-p55, and p75 receptors.

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Discussion 

The present study demonstrates that fatigue is highly prevalent in this cohort of long-term lymphoma survivors treated with ABMT. The differences in levels of fatigue between the patient population and the reference group are highly significant. Among patients cured for Hodgkin's disease,17 the level of fatigue was found to be between the present ABMT cohort and the reference population. It has been postulated that fatigue in the HDS survivors may reduce their quality of life significantly17 and also reduce their working ability.35 Taking these findings into consideration, the high level of fatigue was expected. However, the findings should be interpreted with caution due to the relatively small sample size.

A general tendency was found towards reduced HRQL as compared to the reference populations. Similar findings have been reported in several other studies following patients treated with high-dose therapy.6, 7, 36 However, the differences in the HRQL are smaller than for fatigue. This finding may indicate that fatigue is one of the most distressing subjective side effects after ABMT for lymphoma.

The fatigue scale within the EORTC QLQ-C30 did not pick up a significant difference between the ABMT patients and the reference population. This finding might indicate that the 3-item scale within the EORTC QLQ-C30 is not sensitive enough, or it may measure other domains of fatigue than the FQ does. The latter explanation does not seem reasonable because the content of the EORTC QLQ-C30 fatigue scale is very similar to some of the items within the physical fatigue scale.

To investigate possible explanations for persisting fatigue, two major lines were followed, an immunological and an endocrine. Weak relationships were found between serum levels of sTNFR, TNF, and IL-6 on one hand and fatigue on the other. This was not an unexpected finding, since the levels of cytokines were not elevated in our patients. In previous studies, increased levels of cytokines have been found in patients with malignant lymphoma.37, 38, 39

It has been postulated that cytokines may produce fatigue in humans.20, 21, 23 In a study of 70 patients with chronic fatigue syndrome (CFS), immune dysregulation, with particular focus on dysregulation in TNF expression, was proposed as a possible biological marker of fatigue.40 The findings in the present study were consistent with previous data on immune dysregulation among patients with CFS.41, 42 In another study, elevated serum levels of IL-1 during radiotherapy was found in patients with prostatic cancer at the same time as they reported high level of fatigue.22 In contrast, Morant43 did not find any correlations between fatigue on the one hand and TNF, IL-1, IL-2, IL-6, sIL-1, and sIL-2 on the other. A direct comparison between our study and the above mentioned studies might be difficult due to differences in patient cohort, different methods of measuring fatigue, and different methods used to measure cytokines.

Even if no differences were found in levels of cytokines between patients and controls in our study, the hypothesis of long-term effects of cytokines on fatigue should not be rejected. There may be other cytokines of interest, such as IL-1 and IL-2. The effects on the central nervous system, on muscles, and on the endocrine system after long-term exposure of cytokines would be of special interest to investigate in the oncology population.

A gender difference has been shown for fatigue16 and HRQL29 in the reference population. In the ABMT cohort, the gender differences were large compared to the findings in the normal population. The gender differences were most pronounced for physical fatigue, which was reported by women to be significantly higher than men. The explanation for this difference is unknown. It might theoretically be related to both biological and/or psychological factors.

A highly significant difference also was observed in the younger female group (15–39 years) compared to women aged 40–60 years. Gonadal dysfunction with elevated FSH and reduced levels of estradiol was found in the majority of the women, but an association with fatigue failed to appear. From a clinical perspective, the high prevalence of ovarian dysfunction is of great importance. Loss of ovarian function occurs in all women immediately after autologous and allogenic bone marrow transplantation and is caused by injuries to the ovaries.44 In a recent study, recovery of ovarian function was found in one-third of the patients, and was predicted by younger age. Total body irradiation (TBI), however, seemed to have a negative effect on recovery of ovarian function.24 In our study population, 93% of the women (n = 14) received TBI and cyclophosphamide, one of the most toxic regimens for ovaries. The lack of association between fatigue and the endocrine function in our patients may be due to a combination of the very high prevalence of fatigue and reduced gonadal function, and a very small sample size. It would also have been of interest to measure testosterone among the women. It is likely that testosterone levels are impaired in women with gonadal dysfunction. Long-term hormone therapy with estradiol and testosterone is reported to have a positive effect on loss of energy in some women.45 The findings suggest further follow-up studies of cancer survivors, which should measure the development of fatigue and altered gonadal function over time.

Neurotoxicity is an important issue for survivors after high-dose therapy. In several studies, cognitive impairments have been associated with TBI4, 48 as well as with high-dose chemotherapy.3 Methotrexate is considered to be one of the most neurotoxic drugs. Reduced cognitive functioning among cancer survivors has been reported in several studies46, 47 and may be related to fatigue, especially mental fatigue. In our study, cognitive function, as measured by the EORTC-QLQ-C30, was significantly reduced compared to the general population (Table 3), and correlated significantly with fatigue (r = 0.52, p < 0.01; data not presented). In a cross-sectional study, it might be difficult to determine whether cognitive impairments are related to the treatment or to pre-existing cognitive problems. However, half of the patients received high-dose methotrexate, and some also received methotrexate intrathecally before the ABMT. Patients who received high-dose methotrexate as a preparative regimen were more fatigued and reported reduced cognitive functioning, as compared to patients who did not receive this type of treatment. Cognitive function items are increasingly included in quality of life measures. The validity of a brief cognitive function scale, like the one included in EORTC-QLQ-C30, is questioned.46 Studies among cured lymphoma patients have shown that their reports of memory and concentration problems appear to reflect affective disorder and mental fatigue. Using well validated objective neuropsychological tests is recommended for assessing higher mental function.3, 47

In the absence of information about psychiatric distress, this study is somewhat limited by the uncertainty of the constitution of fatigue. A relation between negative affect and fatigue has been suggested, and depression in particular is considered to be a contributor to fatigue.35 In a study of Hodgkin's disease survivors, chronic fatigue was associated with increased levels of anxiety and depression.49 However, no association between previous psychiatric morbidity and fatigue was found. In our study, we found moderate correlation between fatigue and mental distress assessed by EORTC-QLQ-C30 (r = −0.63, −0.52, and −0.62, PF, MF, and TF, respectively; p = 0.01). The relationship between fatigue and psychiatric distress is far from clear. Both biological correlates and the relation to psychiatric disorders should be explored in further studies of fatigue in cancer patients.

This study has shed light on a prevalent, but poorly understood, phenomena—fatigue—in patients cured of cancer. Fatigue is multidimensional, and the pathophysiology remains uncertain. Significant endocrinological or immunological associations with fatigue could not be demonstrated in the present study. Because high-dose chemotherapy for cancer aims to achieve long-term survival and should allow patients to regain an acceptable life style after completion of treatment, recognition and investigation of fatigue after cancer treatment should be addressed in future research.

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Acknowledgements 

Financial support for this study was provided by Janssen-Cilag AS. A special thanks to the Norwegian Radium Hospital, Department of Oncology, for allowing us the examination of their patients.

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PII: S0885-3924(00)00144-5

Journal of Pain and Symptom Management
Volume 19, Issue 6 , Pages 446-456, June 2000

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